Biomaterial-Stem Cell Approaches to Augment Regeneration

Abstract

Diseases affecting striated muscle are prevalent and deadly in both the Western and developing worlds. Such diseases include peripheral arterial disease and coronary artery disease, characterized by reduced blood flow to extremities and heart muscle, respectively, all of which manifest as reduced function & quality-of-life. Although promising in animal models, many clinical trials of stem cell therapy have yielded modest results at best. Growing evidence suggests that in a disease state, improvements in local environments using natural methods that already exist in the body hold great promise for supporting recovery and regeneration. This may be accomplished by exploiting natural progenitor cell functions and interactions with endogenous extracellular matrix (ECM) components, pro-regenerative cytokines and ligands. This thesis uses ECM-mimicking, collagen-based matrices to improve the regenerative response. Specifically, such a matrix is demonstrated to improve the potency of ex vivo expanded circulating angiogenic cells for treatment of ischemic muscle (Chapter 2). Matrices were also functionalized to release chemoattractant molecules to improve the recruitment of progenitor cells (Chapter 3) and to present progenitor cell-binding ligands for improved cell retention in ischemic muscle (Chapter 4), with the ultimate goal of restoring perfusion. Matrices were also observed to improve muscle function and augment muscle regeneration in models of ischemic and dystrophic muscle (Chapters 4 & 5). The results of this thesis provide insights into the ability to modulate regeneration in vivo with treatment of biomaterials that have been designed to exploit and amplify progenitor cell responses. Specifically, this thesis contains some of the first reports for the use of ECM-based biomaterials to stimulate passive enrichment of circulating angiogenic cells, functional regeneration of muscle, and a potential method of benefitting from necrosis. These data provide an interesting pilot perspective on improvements or alternatives to cell therapy, and future studies will seek to better tune these prospective therapies so that one day they may be clinically available.